Research Article Flutamide-Loaded Zein Nanocapsule Hydrogel, a Promising Dermal Delivery System for Pilosebaceous Unit Disorders Marwa Ahmed Sallam 1,3 and Ahmed O. Elzoghby 1,2 Received 5 March 2018; accepted 24 May 2018 Abstract. Zein is a naturally occurring corn protein having similarity to skin keratin. Owing to its hydrophobicity and biodegradability, zein nanocarriers are promising drug delivery vehicles for hydrophobic dermatological drugs. In this study, zein-based nanocapsules (ZNCs) were exploited for the first time as dermal delivery carriers for flutamide (FLT), an antiandrogen used for the management of pilosebasceous unit disorders. FLT-loaded ZNC of appropriate particle size and negative surface charge were prepared by nanoprecipitation method. The dermal permeation and skin retention of FLT from ZNCs were studied in comparison to corresponding nanoemulsion (NE) and hydroalcoholic drug solution (HA). ZNCs showed a significantly lower permeation flux compared to NE and HA while increasing the skin retention of FLT. Confocal laser scanning microscopy (CLSM) demonstrated the follicular localization of the fluorescently labeled NCs. The incorporation of NCs in chitosan gel or Carbomer® 934 gel was studied. Carbomer® gel increased the skin retention of FLT compared to chitosan gel. Accordingly, Carbomer® hydrogel embedding FLT-loaded ZNCs is a promising inexpensive, biocompatible dermal delivery nanocarrier for localized therapy of PSU disorders suitable for application on oily skin. KEY WORDS: zein; pilosebaceous unit; confocal imaging; follicular targeting; flutamide. INTRODUCTION Pilosebaceous unit (PSU) disorders including acne and androgenic alopecia are due to excess local activity of androgens, particularly dihydrotestosterone (DHT) in the PSU. These usually affect the patients performance particu- larly their self-confidence. Acne vulgaris is the most common disorder affecting the human skin during onset of puberty (1). Its treatments include antibiotics, antiseborrheic medications, retinoids, and antiandrogen medications (2). Androgenetic alopecia (AA), commonly referred to as male pattern baldness, is a form of hair loss affecting either males or females. Oral antiandrogens, which reduce sebum secretion, are used for the treatment of severe acne in females as well as AA. However, systemic treatment is associated with severe side effects which limit the success of the therapy (3). FLT is a peripheral nonsteroidal selective androgen antagonist of expected pharmacological activity in the PSU (4,5). It inhibits receptors binding of androgens. A recent comparative, double-blind clinical trial study demonstrated that FLT was more effective than a combination of cyproter- one–estradiol in the treatment of acne including both inflammatory and non-inflammatory lesions (6). A study on 101 patients reported improvement in alopecia scores that lasted up to 2 years. However, many patients dropped out of the study because of hepatic dysfunction (7). The side effects associating oral therapy necessitates new treatment options for such skin diseases by local application of the medication which would probably improve the drug targeting to its desired site of action and overcome the side effects associating its oral use. Many nanotechnological approaches were performed to enhance drug deposition in the PSU (8–10). These have reported for adapalene ( 11 , 12 ), isotretinoin, and antiandrogens (13). Polymeric nanocapsules are submicrometric vesicular carriers composed of an oily core surrounded by an ultrathin polymeric wall (14,15). They have been widely used for topical applications, showing various advantages over con- ventional systems (16,17). However, literature survey re- vealed that the majority of the previous approaches focused on the use of synthetic polymers which are either non- biodegradable as Eudragits (18) or relatively expensive as Electronic supplementary material The online version of this article (https://doi.org/10.1208/s12249-018-1087-z) contains supplementary material, which is available to authorized users. 1 Industrial Pharmacy Department, Faculty of Pharmacy, Alexandria University, 1 Midan Alkhartoom square, Alazarita, Alexandria, Egypt. 2 Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria, 21521, Egypt. 3 To whom correspondence should be addressed. (e–mail: dr_marwasallam@yahoo.com; marwa.salam@alexu.edu.eg) AAPS PharmSciTech ( # 2018) DOI: 10.1208/s12249-018-1087-z 1530-9932/18/0000-0001/0 # 2018 American Association of Pharmaceutical Scientists